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Neuronal Injury Reviews: 2003

(82 References)

Ahlemeyer, B. and J. Krieglstein (2003). "Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease." Pharmacopsychiatry 36 Suppl 1: S8-14.

            The standardized Ginkgo biloba extract EGb 761(definition see editorial) has been shown to produce neuroprotective effects in different in vivo and in vitro models. Since EGb 761 is a complex mixture containing flavonoid glycosides, terpene lactones (non-flavone fraction) and various other constituents, the question arises as to which of these compounds mediates the protective activity of EGb 761. Previous studies have demonstrated that the non-flavone fraction was responsible for the antihypoxic activity of EGb 761. Thus, we examined the neuroprotective and anti-apoptotic ability of the main constituents of the non-flavone fraction, the ginkgolides A, B, C, J and bilobalide. In focal cerebral ischemia models, the administration of bilobalide (5-20 mg/kg, s. c.) 60 min before ischemia dose-dependently reduced the infarct area in mouse brain and the infarct volume in rat brain 2 days after the onset of the injury. 30 minutes of pretreatment with ginkgolide A (50 mg/kg, s. c.) and ginkgolide B (100 mg/kg, s. c.) reduced the infarct area in the mouse model of focal ischemia. In primary cultures of hippocampal neurons and astrocytes from neonatal rats, ginkgolide B (1 microM) and bilobalide (10 microM) protected the neurons against damage caused by glutamate (1 mM, 1 h) as evaluated by trypan blue staining. In addition, bilobalide (0.1 microM) was able to increase the viability of cultured neurons from chick embryo telencepalon when exposed to cyanide (1 mM, 1h). Furthermore, we attempted to find out whether ginkgolides A, B, and J and bilobalide were also able to inhibit neuronal apoptosis (determined by nuclear staining with Hoechst 33 258 and TUNEL-staining). Ginkgolide B (10 microM), ginkgolide J (100 microM) and bilobalide (1 microM) reduced the apoptotic damage induced by serum deprivation (24h) or treatment with staurosporine (200 nM, 24h) in cultured chick embryonic neurons. Bilobalide (100 microM) rescued cultured rat hippocampal neurons from apoptosis caused by serum deprivation (24h), whereas ginkgolide B (100 microM) and bilobalide (100 microM) reduced apoptotic damage induced by staurosporine (300 nM, 24h). Ginkgolide A failed to affect apoptotic damage neither in serum-deprived nor in staurosporine-treated neurons. The results suggest that some of the constituents of the non-flavone fraction of EGb 761 possess neuroprotective and anti-apoptotic capacity, and that bilobalide is the most potent one. In contrast, ginkgolic acids (100-500 microM) induced neuronal death, which showed features of apoptosis as well as of necrosis, but these constituents were removed from EGb 761 below an amount of 0.0005 %. Taking together, there is experimental evidence for a neuroprotective effect of EGb 761 that agrees with clinical studies showing the efficacy of an oral treatment in patients with mild and moderate dementia.

Albensi, B. C. and D. Janigro (2003). "Traumatic brain injury and its effects on synaptic plasticity." Brain Inj 17(8): 653-63.

            Animal models have been used to simulate the effects of human head trauma. Some of these models have been further utilized to explore how trauma affects specific mechanisms of synaptic plasticity, a cellular model for memory consolidation. Unfortunately, these studies have been more limited in number in spite of their importance for understanding alterations in synaptic plasticity and memory impairments in trauma patients. Research in this area includes well characterized trauma models, genetically engineered animals and neuroprotective studies. One largely ignored but important idea that is entertained here is that trauma may be a crucial aetiological factor for the loss of potassium homeostasis. Moreover, high extracellular potassium has been shown to promote abnormal expression of hippocampal synaptic plasticity due to K(+)-induced glutamate release, thus showing important relationships among trauma, glia, potassium and synaptic plasticity. Collectively, this mini review surveys investigations of head trauma involving altered mechanisms of synaptic plasticity and how trauma may be related to increased risk for dementia.

Anderson, M. F., F. Blomstrand, et al. (2003). "Astrocytes and stroke: networking for survival?" Neurochem Res 28(2): 293-305.

            Astrocytes are now known to be involved in the most integrated functions of the central nervous system. These functions are not only necessary for the normally working brain but are also critically involved in many pathological conditions, including stroke. Astrocytes may contribute to damage by propagating spreading depression or by sending proapoptotic signals to otherwise healthy tissue via gap junction channels. Astrocytes may also inhibit regeneration by participating in formation of the glial scar. On the other hand, astrocytes are important in neuronal antioxidant defense and secrete growth factors, which probably provide neuroprotection in the acute phase, as well as promoting neurogenesis and regeneration in the chronic phase after injury. A detailed understanding of the astrocytic response, as well as the timing and location of the changes, is necessary to develop effective treatment strategies for stroke patients.

Bach-y-Rita, P. (2003). "Theoretical basis for brain plasticity after a TBI." Brain Inj 17(8): 643-51.

            Evidence has been accumulating that the brain can reorganize extensively after damage and that reorganization can be obtained even many years after the trauma with appropriate late rehabilitation. An understanding of the brain plasticity mechanisms should lead to more effective rehabilitation and neuropharmacology. In this communication, several emerging concepts with supporting experimental evidence have been presented. These include non-synaptic diffusion neurotransmission, extracellular space volume fraction, neurotransmitters, regeneration and neurogenesis and multiplexing.

Bhave, G. and R. W. t. Gereau (2003). "Growing pains: the cytoskeleton as a critical regulator of pain plasticity." Neuron 39(4): 577-9.

            Inflammatory mediators act on peripheral sensory neurons to produce pain and hypersensitivity after tissue injury. In this issue of Neuron, Dina et al. report that inflammatory mediators, such as epinephrine and prostaglandins, appear to couple to specific G protein-coupled receptor signaling pathways through plastic interactions with the cytoskeleton.

Blomgren, K., C. Zhu, et al. (2003). "Mitochondria and ischemic reperfusion damage in the adult and in the developing brain." Biochem Biophys Res Commun 304(3): 551-9.

            The developing and the adult brain respond in similar ways to ischemia, but also display clear differences. For example, the relative contributions of necrosis and apoptosis to neuronal death may be different, such that apoptotic mechanisms would be more prevalent in the developing brain. During normal development, more than half of the neurons in some brain regions are removed through apoptosis, and effectors like caspase-3 are highly upregulated in the immature brain. Mitochondria are pivotal regulators of cell death through their role in energy production and calcium homeostasis, their capacity to release apoptogenic proteins and to produce reactive oxygen species. This review will summarize some of the current studies dealing with mitochondria-related mechanisms of ischemic brain damage, with special reference to developmental aspects.

Browning, K. N. and D. Mendelowitz (2003). "Musings on the wanderer: what's new in our understanding of vago-vagal reflexes?: II. Integration of afferent signaling from the viscera by the nodose ganglia." Am J Physiol Gastrointest Liver Physiol 284(1): G8-14.

            To understand vago-vagal reflexes, one must have an appreciation of the events surrounding the encoding, integration, and central transfer of peripheral sensations by vagal afferent neurons. A large body of work has shown that vagal afferent neurons have nonuniform properties and that distinct subpopulations of neurons exist within the nodose ganglia. These sensory neurons display a considerable degree of plasticity; electrophysiological, pharmacological, and neurochemical properties have all been shown to alter after peripheral tissue injury. The validity of claims of selective recordings from populations of neurons activated by peripheral stimuli may be diminished, however, by the recent demonstration that stimulation of a subpopulation of nodose neurons can enhance the activity of unstimulated neuronal neighbors. To better understand the neurophysiological processes occurring after vagal afferent stimulation, it is essential that the electrophysiological, pharmacological, and neurochemical properties of nodose neurons are correlated with their sensory function or, at the very least, with their specific innervation target.

Burnett, A. L. (2003). "Neuroprotection and nerve grafts in the treatment of neurogenic erectile dysfunction." J Urol 170(2 Pt 2): S31-4; discussion S34.

            PURPOSE: The rationale for protecting the nerve supply of the penis derives mainly from the fact that neurological injury or disease states involving this organ commonly result in erectile dysfunction. Novel directions in the management of neurogenic erectile dysfunction that pertain specifically to sustaining penile neuronal function are described. MATERIALS AND METHODS: The review constitutes a summary of neuroprotective strategies for penile erection that are under investigation at the basic science level or have been brought to clinical practice. The basic exercise consisted primarily of a literature search using the National Library of Medicine PubMed Services, with references made to such keywords as nerve grafts, nerve growth factors, neuroprotection and nerve regeneration. RESULTS: Primary advances in this field have centered on repairing structural defects and restoring the functional integrity of the cavernous nerves of the penis. In the former autologous nerve conduits, such as sural nerve grafts, have been explored and used prominently in the context of radical prostatectomy. In the latter diverse neurotrophic treatments have been investigated, with progress mostly limited to animal models of cavernous nerve injury. Basic concepts and ongoing developments in the neurobiology of axonal regeneration were identified as being applicable to this area of neurourology. CONCLUSIONS: Because neurogenic origins represent a leading categorical cause of erectile dysfunction, the importance of developing and applying treatment approaches to alleviate neuropathic effects on the erectile tissue of the penis is certain. Medical and surgical innovations for preserving and reconstituting the functional nerve supply of the penis offer great promise in the management of erectile dysfunction.

Byers, M. R., H. Suzuki, et al. (2003). "Dental neuroplasticity, neuro-pulpal interactions, and nerve regeneration." Microsc Res Tech 60(5): 503-15.

            This review covers current information about the ability of dental nerves to regenerate and the role of tooth pulp in recruitment of regenerating nerve fibers. In addition, the participation of dental nerves in pulpal injury responses and healing is discussed, especially concerning pulp regeneration and reinnervation after tooth replantation. The complex innervation of teeth is highly asymmetric and guided towards specific microenvironments along blood vessels or in the crown pulp and dentin. Pulpal products such as nerve growth factor are distributed in the same asymmetric gradients as the dentinal sensory innervation, suggesting regulation and recruitment of those nerve fibers by those specific factors. The nerve fibers have important effects on pulpal blood flow and inflammation, while their sprouting and cytochemical changes after tooth injury are in response to altered pulpal cytochemistry. Thus, their pattern and neuropeptide intensity are indicators of pulp status, while their local actions continually affect that status. When denervated teeth are injured, either by pulp exposure on the occlusal surface or by replantation, they have more pulpal necrosis than occurs for innervated teeth. However, small pulp exposures on the side of denervated crowns or larger lesions in germ-free animals can heal well, showing the value of postoperative protection from occlusal trauma or from infection. Current ideas about dental neuroplasticity, neuro-pulpal interactions, and nerve regeneration are related to the overall topics of tooth biomimetics and pulp/dentin regeneration.

Calabresi, P., L. M. Cupini, et al. (2003). "Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia." Ann Neurol 53(6): 693-702.

            Several new antiepileptic drugs (AEDs) have been introduced for clinical use recently. These new AEDs, as did the classic AEDs, target multiple cellular sites both pre- and postsynaptically. The major common goal of the pharmacological treatment using AEDs is to counteract abnormal brain excitability by either decreasing excitatory transmission or enhancing neuronal inhibition. Interestingly, an excessive release of excitatory amino acids and a reduced neuronal inhibition also occur in brain ischemia. Thus, recently, the use of AEDs as a possible neuroprotective strategy in brain ischemia is receiving increasing attention, and many AEDs have been tested in animal models of stroke, providing encouraging results. Experimental studies utilizing global or focal ischemia in rodents have provided insights into the possible neuroprotective action of the various AEDs. However, the implication of these studies in the treatment of acute stroke in humans is not always direct. In fact, various clinical studies with drugs targeting the same voltage- and ligand-gated channels modulated by most of the AEDs failed to show neuroprotection. The differential mechanisms that underlie the development of focal ischemic injury in experimental animal models versus human stroke require further investigation to open a new therapeutic perspective for neuroprotection that might be applicable in the future.

Carmichael, S. T. (2003). "Plasticity of cortical projections after stroke." Neuroscientist 9(1): 64-75.

            Ischemic stroke produces cell death and disability, and a process of repair and partial recovery. Plasticity within cortical connections after stroke leads to partial recovery of function after the initial injury. Physiologically, cortical connections after stroke become hyperexcitable and more susceptible to the induction of LTP Stroke produces changes in the distribution and laterality of sensory, motor, and language representations within the brain that correlate with functional recovery. Anatomically, ischemic lesions induce axonal sprouting within local, intracortical projections and long distance, interhemispheric projections. This postischemic axonal sprouting establishes substantially new patterns of cortical connections with de-afferented or partially damaged brain areas. Axonal sprouting after ischemic lesions is induced by a transient pattern of synchronous, low-frequency neuronal activity in a network of cortical areas connected to the infarct. This pattern of neuronal activity that induces axonal sprouting in the adult after ischemic lesions resembles that seen in the developing brain during axonal elongation and synaptogenesis. Thus, stroke induces a process of remapping and reconnection within the adult brain through changes in neuronal activity that may involve a reactivation of developmental programs in areas connected to the infarct.

Chen, Y. and R. A. Swanson (2003). "Astrocytes and brain injury." J Cereb Blood Flow Metab 23(2): 137-49.

            Astrocytes are the most numerous cell type in the central nervous system. They provide structural, trophic, and metabolic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions during brain ischemia and other insults can critically influence neuron survival. Astrocyte functions that are known to influence neuronal survival include glutamate uptake, glutamate release, free radical scavenging, water transport, and the production of cytokines and nitric oxide. Long-term recovery after brain injury, through neurite outgrowth, synaptic plasticity, or neuron regeneration, is influenced by astrocyte surface molecule expression and trophic factor release. In addition, the death or survival of astrocytes themselves may affect the ultimate clinical outcome and rehabilitation through effects on neurogenesis and synaptic reorganization.

Chernoff, E. A., D. L. Stocum, et al. (2003). "Urodele spinal cord regeneration and related processes." Dev Dyn 226(2): 295-307.

            Urodele amphibians, newts and salamanders, can regenerate lesioned spinal cord at any stage of the life cycle and are the only tetrapod vertebrates that regenerate spinal cord completely as adults. The ependymal cells play a key role in this process in both gap replacement and caudal regeneration. The ependymal response helps to produce a different response to neural injury compared with mammalian neural injury. The regenerating urodele cord produces new neurons as well as supporting axonal regrowth. It is not yet clear to what extent urodele spinal cord regeneration recapitulates embryonic anteroposterior and dorsoventral patterning gene expression to achieve functional reconstruction. The source of axial patterning signals in regeneration would be substantially different from those in developing tissue, perhaps with signals propagated from the stump tissue. Examination of the effects of fibroblast growth factor and epidermal growth factor on ependymal cells in vivo and in vitro suggest a connection with neural stem cell behavior as described in developing and mature mammalian central nervous system. This review coordinates the urodele regeneration literature with axial patterning, stem cell, and neural injury literature from other systems to describe our current understanding and assess the gaps in our knowledge about urodele spinal cord regeneration.

Denicourt, C. and S. F. Dowdy (2003). "Protein transduction technology offers novel therapeutic approach for brain ischemia." Trends Pharmacol Sci 24(5): 216-8.

            Transient or permanent reduction in cerebral blood flow following ischemia can lead to severe and irreversible tissue damage to the brain. Emerging biochemical evidence suggests a role for apoptosis in neuronal death following cerebral ischemia. Despite the abundance of studies on the subject, therapeutic interventions for ischemia-related cell injury have so far proved disappointing in clinical trials. Recently, four new, exciting studies reported the use of protein transduction technology to deliver anti-apoptotic molecules to protect neuronal cells following ischemic stroke in vivo. These studies offer new avenues for the treatment and prevention of cell death following brain injuries.

Derakhshan, I. (2003). "Callosum and movement control: case reports." Neurol Res 25(5): 538-42.

            This article explores the role of directionality of callosal traffic (codified as handedness), based on personal clinical observations and a critical review of the literature. Based on this evidence, a technical definition of handedness is offered as opposed to the behavioral method in use until now. In the vast majority of right-handers neural and behavioral handedness match. The situation is the opposite in left-handers where two thirds of them are wired to be right-handers, causing the well-known heterogeneity seen in left-handed cohorts. The callosum-length proximity of the dominant side of the body to the command center in the major hemisphere is the source of its neurophysiological superiority compared to the nondominant side. Clinical syndromes in which the new scheme are manifested are reviewed, indicating the existence of an excitatory influence by the neuronal aggregate devoted to voluntary actions, housed in the major hemisphere, on their counterparts in the minor hemisphere. The latter is exclusively devoted to volitional movements occurring on the nondominant side. Thus, it is the directionality of callosal traffic that is responsible for cerebral asymmetries seen in the motor realm.

Dineley, K. E., T. V. Votyakova, et al. (2003). "Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration." J Neurochem 85(3): 563-70.

            An increasing body of evidence suggests that high intracellular free zinc promotes neuronal death by inhibiting cellular energy production. A number of targets have been postulated, including complexes of the mitochondrial electron transport chain, components of the tricarboxylic acid cycle, and enzymes of glycolysis. Consequences of cellular zinc overload may include increased cellular reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and reduced cellular ATP levels. Additionally, zinc toxicity might involve zinc uptake by mitochondria and zinc induction of mitochondrial permeability transition. The present review discusses these processes with special emphasis on their potential involvement in brain injury.

Fern, R. (2003). "Variations in spare electron transport chain capacity: The answer to an old riddle?" J Neurosci Res 71(6): 759-62.

            Several neurological diseases involve focal injury of specific brain structures. Poisons of the electron transport chain complexes (ETCC) can also produce selective injury of brain structures when given systemically and have been implicated in the development of neurological disease. Why ETCC poisons damage particular brain regions is unclear. Calculations of the relative ETCC expression level to glucose utilization rate (GUR) ratio from published observations here reveal that a low ETCC/GUR ratio predisposes a brain structure to injury by a poison of that complex. While GUR can rise with increased neuronal activity, ETCC expression is fixed in the short term. A high ETCC/GUR therefore represents surplus ETCC capacity, allowing for increased ATP generation with short-term increases in demand. A low ETCC/GUR indicates the opposite and will lead to energy failure when the specific ETCC is poisoned. These observations may explain why cyanide, a specific ETCC (IV) inhibitor, can produce selective injury of white matter, which has the lowest ETCC (IV)/GUR found in the brain. They are also consistent with the selective damage of the striatum produced by poisons such as rotenone, a form of injury implicated in Parkinson's disease. The striatum has a low ETCC (I)/GUR ratio, whereas rotenone is a selective ETCC (I) inhibitor.

Forster, H. V. (2003). "Plasticity in the control of breathing following sensory denervation." J Appl Physiol 94(2): 784-94.

            The purpose of this manuscript is to review the results of studies on the recovery or plasticity following a denervation- or lesion-induced change in breathing. Carotid body denervation (CBD), lung denervation (LD), cervical (CDR) and thoracic (TDR) dorsal rhizotomy, dorsal spinal column lesions, and lesions at pontine, medullary, and spinal sites all chronically alter breathing. The plasticity after these is highly variable, ranging from near complete recovery of the peripheral chemoreflex in rats after CBD to minimal recovery of the Hering-Breuer inflation reflex in ponies after LD. The degree of plasticity varies among the different functions of each pathway, and plasticity varies with the age of the animal when the lesion was made. In addition, plasticity after some lesions varies between species, and plasticity is greater in the awake than in the anesthetized state. Reinnervation is not a common mechanism of plasticity. There is evidence supporting two mechanisms of plasticity. One is through upregulation of an alternate sensory pathway, such as serotonin-mediated aortic chemoreception after CBD. The second is through upregulation on the efferent limb of a reflex, such as serotonin-mediated increased responsiveness of phrenic motoneurons after CDR, TDR, and spinal cord injury. Accordingly, numerous components of the ventilatory control system exhibit plasticity after denervation or lesion-induced changes in breathing; this plasticity is uniform neither in magnitude nor in underlying mechanisms. A major need in future research is to determine whether "reorganization" within the central nervous system contributes to plasticity following lesion-induced changes in breathing.

Fukuda, S. and G. J. del Zoppo (2003). "Models of focal cerebral ischemia in the nonhuman primate." Ilar J 44(2): 96-104.

            Ischemic stroke is a uniquely human disease syndrome. Models of focal cerebral ischemia developed in nonhuman primates provide clinically relevant platforms for investigating pathophysiological alterations associated with ischemic brain injury, microvascular responses, treatment responses, and clinically relevant outcomes that may be appropriate for ischemic stroke patients. A considerable number of advantages attend the use of nonhuman primate models in cerebral vascular research. Appropriate development of such models requires neurosurgical expertise to produce single or multiple vascular occlusions. A number of experimentally and clinically accessible outcomes can be measured, including neurological deficits, neuron injury, evidence of non-neuronal cell injury, infarction volume, real-time imaging of injury development, vascular responses, regional cerebral blood flow, microvascular events, the relation between neuron and vascular events, and behavioral outcomes. Nonhuman primate models of focal cerebral ischemia provide excellent opportunities for understanding the vascular and cellular pathophysiology of cerebral ischemic injury, which resembles human ischemic stroke, and the appropriate study of pharmacological interventions in a human relevant setting.

Gibbs, S. M. (2003). "Regulation of neuronal proliferation and differentiation by nitric oxide." Mol Neurobiol 27(2): 107-20.

            Many studies have revealed the free radical nitric oxide (NO) to be an important modulator of vascular and neuronal physiology. It also plays a developmental role in regulating synapse formation and patterning. Recent studies suggest that NO may also mediate the switch from proliferation to differentiation during neurogenesis. Many mechanisms of this response are conserved between neuronal precursor cells and the cells of the vascular system, where NO can inhibit the proliferative response of endothelial and smooth-muscle cells to injury. In cultured neuroblastoma cells, NO synthase (NOS) expression is increased in the presence of various growth factors and mitogens. Subsequent production of NO leads to cessation of cell division and the acquisition of a differentiated phenotype. The inhibitory action of NO on neuroblast proliferation has also been demonstrated in vivo for vertebrate and invertebrate nervous systems, as well as in the adult brain. Potential downstream effectors of NO include the second messenger cyclic GMP, activation of the tumor-suppressor genes p53 and Rb, and the cyclin-dependent kinase inhibitor p21. These studies highlight a new role for NO in the nervous system, as a coordinator of proliferation and patterning during neural development and adult neurogenesis.

Goldstein, L. B. (2003). "Neuropharmacology of TBI-induced plasticity." Brain Inj 17(8): 685-94.

            PRIMARY OBJECTIVE: The purpose of this report is to review both fundamental studies in laboratory animals and preliminary clinical data suggesting that certain drugs may affect behavioural recovery after brain injury. MAIN OUTCOMES AND RESULTS: Laboratory studies show that systemically-administered drugs that affect specific central neurotransmitters including norepinephrine and GABA influence affect recovery in a predictable manner. Although some drugs such as d-amphetamine have the potential to enhance recovery, others such as neuroleptics and other central dopamine receptor antagonists, benzodiazepines and the anti-convulsants phenytoin and phenobarbital may be detrimental. In one study, 72% of patients with traumatic brain injury received one or a combination of the drugs that may impair recovery based on both animal experiments and studies in recovering stroke patients. CONCLUSIONS: Until the true impact of these classes of drugs are better understood, care should be exercised in the use of medications that may interfere with the recovery process in patients with traumatic brain injury. Additional research needs to be completed before the clinical efficacy of drugs that may enhance recovery can be established.

Goshgarian, H. G. (2003). "The crossed phrenic phenomenon: a model for plasticity in the respiratory pathways following spinal cord injury." J Appl Physiol 94(2): 795-810.

            Hemisection of the cervical spinal cord rostral to the level of the phrenic nucleus interrupts descending bulbospinal respiratory pathways, which results in a paralysis of the ipsilateral hemidiaphragm. In several mammalian species, functional recovery of the paretic hemidiaphragm can be achieved by transecting the contralateral phrenic nerve. The recovery of the paralyzed hemidiaphragm has been termed the "crossed phrenic phenomenon." The physiological basis for the crossed phrenic phenomenon is as follows: asphyxia induced by spinal hemisection and contralateral phrenicotomy increases central respiratory drive, which activates a latent crossed respiratory pathway. The uninjured, initially latent pathway mediates the hemidiaphragm recovery by descending into the spinal cord contralateral to the hemisection and then crossing the midline of the spinal cord before terminating on phrenic motoneurons ipsilateral and caudal to the hemisection. The purpose of this study is to review work conducted on the crossed phrenic phenomenon and to review closely related studies focusing particularly on the plasticity associated with the response. Because the review deals with recovery of respiratory muscles paralyzed by spinal cord injury, the clinical relevance of the reviewed studies is highlighted.

Graham, S. H. and R. W. Hickey (2003). "Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death." Arch Neurol 60(4): 628-30.

Hama, T. (2003). "[Molecule for neuronal survival in the brain--identification and characterization of novel glycomembrane-protein p40BBP]." Seikagaku 75(7): 588-96.

Harry, G. J. and C. Lefebvre d'Hellencourt (2003). "Dentate gyrus: alterations that occur with hippocampal injury." Neurotoxicology 24(3): 343-56.

            Injury to the brain usually manifests not in a diffuse uniform manner but rather with selective sites of damage indicative of differential vulnerability. This question of neuronal susceptibility has been one of major interest both in disease processes as well as damage induced by environmental factors. For experimental examination, brain structures with obvious neuronal subpopulations and organization such as the cerebellum and the hippocampus have offered the most promise. In the hippocampus distinct neuronal populations exist that demonstrate differential vulnerability to various forms of insult including ischemia, excitotoxicity, and environmental factors. The more recent data regarding the presence of neuronal progenitor cells in the subgranular zone of the dentate offers the opportunity to expand such experimental examination to the process of injury-induced neurogenesis. Thus, more recent studies have expanded the examination of the hippocampus to include models of damage to the dentate neurons in addition to the highly vulnerable pyramidal neurons. A number of these models are presented for both human disease and experimental animal conditions. Examination of the responses between these distinct cell populations offers the potential for understanding factors that are critical in neuronal death and survival.

Heida, T. (2003). "Electric field-induced effects on neuronal cell biology accompanying dielectrophoretic trapping." Adv Anat Embryol Cell Biol 173: III-IX, 1-77.

            Trapping neuronal cells may aid in the creation of the cultured neuron probe. The aim of the development of this probe is the creation of the interface between neuronal cells or tissue in a (human) body and electrodes that can be used to stimulate nerves in the body by an external electrical signal in a very selective way. In this way, functions that were (partially) lost due to nervous system injury or disease may be restored. First, a direct contact between cultured neurons and electrodes is created. This is realized using a microelectrode array (MEA) which can be fabricated using standard photolithographic and etching methods. Section 1 gives an overview of the human nervous system, methods for functional recovery focused on the cultured neuron probe, and the prerequisites for culturing neurons on a microelectrode array. An important aspect in the selective stimulation of neuronal cells is the positioning of cells or a small group of cells on top of each of the electrode sites of the MEA. One of the most efficient methods for trapping neuronal cells is to make use of di-electrophoresis (DEP). Dielectrophoretic forces are created when (polarizable) cells are located in nonuniform electric fields. Depending on the electrical properties of the cells and the suspending medium, the DEP force directs the cells towards the regions of high field strength (positive dielectrophoresis; PDEP) or towards regions of minimal field intensities (negative dielectrophoresis; NDEP). Since neurons require a physiological medium with a sufficient concentration of Na+, the medium conductivity is rather high (~ 1.6 S/m). The result is that negative dielectrophoretic forces are created over the entire frequency range. With the use of a planar quadrupole electrode sturcture negative forces are directed so that in the center of this structure cell can be collected. The process of trapping cortical rat neurons is described in Sect. 2 theoretically and experimentally. Medium and cell properties are frequency-dependent due to relaxation processes, which have a direct influence on the strength of the dielectrophorectic force. On the other hand, the nonideal material properties of the gold electrodes and glass substrate largely determine the electric field strength created inside the medium. Especially, the electrode-medium interface results in a significant loss of the imput signal at lower frequencies (< 1 MHz), and thus a reduction of the electric field strength inside the medium. Furthermore, due to the high medium conductivity, the electric field causes Joule heating. Local temperature rises result in local gradients in fluid density, which induces fluid flow. The electrode-medium interface and induced fluid flow are theoretically investigated with the use of modeling techniques such as finite elements modeling. Experimental and theoretical results agreed with each other on the occurrence of the effects described in this section. For the creation of the cultured neuron probe, preservation of cell viability during the trapping process is a prerequisite. Cell viability of dielectrophoretically trapped neurons has to be investigated. The membrane potential induced by the external field plays a crucial role in preservation of cell viability. The membrane can effectively be represented by a capaticance in parallel woth a low conductance; with increasing frequency and /or decreasing field strength the induced membrane potential decreases. At high induced membrane potentials ths representation for the membrane is no longer valid. At this point membrane breakdown occurs and the normally insulating membrane becomes conductive and permeable. The creation of electropores has been proposed in literature to be the cause of this high permeability state. Pores may grow or many small pores may be created which eventually may lead to membrane rupture, and thus cell death. Membrane breakdown may be reversible, but a chemical imbalance created during the high permeability state may still exist after the resealing of the membrane. This may cause cell death after several hours or even days after field application. Section 3 gives a detailed description of membrane breakdown. Since many investigations on electroporation of lipid bilayers and cell membranes are based on uniform electric fields, a finite element model is used to investigate induced membrane potentials in the nonuniform field created by the quadropole electrode structure. Modeling results are presented in cmbination with the results of breakdown experiments using four frequencies in the range from 100 kHz to 1MHz. Radomly positioned neuronals cells were exposed to stepwise increasing electric field strengths. The field strength at which membrane rupture occurred gives an indication of the maximum induced membrane potential. Due to the nonuniformity of the electric field, cell collapse was expected to be position-dependent. However, at 100 kHz cells collapsed at a break down level of about 0.4 V, in contradistinction to findings at higher frequencies where more variation in breakdown levels were found. Model simulations were able to explain the experimental results. For examining whether the neuronal cells trapped by dielectrophoresis were still viable after the trapping process, the frequency range was divided into two ranges. First, a high frequency (14 MHz) and a rather low signal amplitude (3 Vpp) were used to trap cells. At this high frequency the field-induced membrane potential is small according to the theoretical model, and therefore no real damage is expected. The experimental analysis included the investigation of the growth of the neurons, number and length of the processes (dendrites and axons), and the number of outgrowing (~ viable) versus nonoutgrowing (~ nonviable) neural cells. The experimental results agreed with the expectation. The effect of the use of driving signals with lower frequencies and/or higher amplitudes on cell viability was investigated using a staining method as described in the second part of Sect. 4. Survival chances are not directly linked to the estimated maximum induced membrane potential. The frequency of the dield plays an important role, decreasing frequency lowering the chance of survival. A lower frequency limit of 100 kHz is preferable at field strengths less than 80 k V/m, while with increasing field strength this limit shifts towards higher frequencies. The theoretical and experimental results presented in this review form the inception of the development of new electrode structures for trapping neuronal cells on top of each of the electrodes of the MEA. New ways to investigate cell properties and the phenomenon of electroporation using electrokinetic methods were developed that can be exploited in future research linking cell biology to technology.

Heinrich, P. C., I. Behrmann, et al. (2003). "Principles of interleukin (IL)-6-type cytokine signalling and its regulation." Biochem J 374(Pt 1): 1-20.

            The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.

Hong, H. and G. Q. Liu (2003). "Current status and perspectives on the development of neuroprotectants for ischemic cerebrovascular disease." Drugs Today (Barc) 39(3): 213-22.

            The concept of neuroprotection is based on the understanding that delayed neuronal damage occurs after ischemia. Each step along the ischemic cascade provides an opportunity for therapeutic intervention. Based on the excellent results obtained in experimental models of ischemia, many clinical trials have been conducted with different neuroprotective drugs. The results obtained in most studies were negative and in some cases the studies were terminated due to safety problems. However, the mechanisms that underlie the development of ischemic damage are still being discovered, creating new therapeutic possibilities for neuroprotection that might be clinically applicable in the future. This article reviews the mechanisms of ischemic neuronal injury, the mechanism of action of neuroprotective agents, current neuroprotective clinical trials, and probable reasons for the failure of clinical neuroprotection. (c) 2003 Prous Science. All rights reserved.

Hossmann, K. A. (2003). "[Glutamate hypothesis of stroke]." Fortschr Neurol Psychiatr 71 Suppl 1: S10-5.

            Neuronal injury following focal cerebral ischemia is widely attributed to the excitatory effects of glutamate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of this data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurotoxic mechanism. An alternative explanation for glutamate-mediated injury is energy failure due to peri-infarct spreading depression-like depolarizations. These depolarizations cause a sharp increase in metabolic activity and therefore produce a mismatch between blood flow and the oxygen requirements of the tissue. The generation of peri-infarct spreading depressions and the associated metabolic workload can be suppressed by glutamate antagonists. As a result, energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload, rather than interfering with the consequences of a putative excitotoxic injury cascade.

Hsueh, W., M. S. Caplan, et al. (2003). "Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts." Pediatr Dev Pathol 6(1): 6-23.

            Necrotizing enterocolitis (NEC), a disease affecting predominantly premature infants, is a leading cause of morbidity and mortality in neonatal intensive care units. Although several predisposing factors have been identified, such as prematurity, enteral feeding, and infection, its pathogenesis remains elusive. In the past 20 years, we have established several animal models of NEC in rats and found several endogenous mediators, especially platelet-activating factor (PAF), which may play a pivotal role in NEC. Injection of PAF induces intestinal necrosis, and PAF antagonists prevent the bowel injury induced by bacterial endotoxin, hypoxia, or challenge with tumor necrosis factor-a (TNF) plus endotoxin in adult rats. The same is true for lesions induced by hypoxia and enteral feeding in neonatal animals. Human patients with NEC show high levels of PAF and decreased plasma PAF-acetylhydrolase, the enzyme degrading PAF. The initial event in our experimental models of NEC is probably polymorphonuclear leukocyte (PMN) activation and adhesion to venules in the intestine, which initiates a local inflammatory reaction involving proinflammatory mediators including TNF, complement, prostaglandins, and leukotriene C4. Subsequent norepinephrine release and mesenteric vasoconstriction result in splanchnic ischemia and reperfusion. Bacterial products (e.g., endotoxin) enter the intestinal tissue during local mucosal barrier breakdown, and endotoxin synergizes with PAF to amplify the inflammation. Reactive oxygen species produced by the activated leukocytes and by intestinal epithelial xanthine oxidase may be the final pathway for tissue injury. Protective mechanisms include nitric oxide produced by the constitutive (mainly neuronal) nitric oxide synthase, and indigenous probiotics such as Bifidobacteria infantis. The former maintains intestinal perfusion and the integrity of the mucosal barrier, and the latter keep virulent bacteria in check. The development of tissue injury depends on the balance between injurious and protective mechanisms.

Ikeda, K., H. Negishi, et al. (2003). "Antioxidant nutrients and hypoxia/ischemia brain injury in rodents." Toxicology 189(1-2): 55-61.

            Cerebral ischemia and recirculation cause delayed neuronal death in rodents, such as Mongolian gerbils and stroke-prone spontaneously hypertensive rats (SHRSP), which were used as an experimental stroke model. It was documented that an enhanced nitric oxide production, the occurrence of apoptosis, and an attenuated redox regulatory system contribute to the development of delayed neuronal death. Many studies have suggested the beneficial antioxidant effects of antioxidant nutrients such as vitamin E, green tea extract, ginkgo biloba extract, resveratrol and niacin in cerebral ischemia and recirculation brain injury. These results are important in light of an attenuation of the deleterious consequences of oxidative stress in ischemia and recirculation injury.

Inamasu, J., Y. Nakamura, et al. (2003). "Induced hypothermia in experimental traumatic spinal cord injury: an update." J Neurol Sci 209(1-2): 55-60.

            The use of induced hypothermia in the treatment of traumatic spinal cord injury (SCI) has been studied extensively between the 1960s and 1970s. Although the treatment showed some promise, it became less popular by the 1980s, mainly because of its adverse effects. However, a revival of hypothermia in the treatment of traumatic brain injury (TBI) in the last decade has encouraged neuroscientists to conduct experiments to reevaluate the potential benefits of hypothermia in traumatic SCI. All laboratory investigations studying the mechanisms of action and/or the efficacy of induced hypothermia in treating experimental traumatic SCI published in the last decade were reviewed. Although efficacy of hypothermia in improving functional outcome of mild to moderate traumatic SCI has been demonstrated, hypothermia may not be protective against severe traumatic SCI. At present, induced hypothermia has yet to be recognized or approved as a potential treatment having therapeutic value for traumatic SCI in humans. The continued search for a possible synergistic effect of induced hypothermia and pharmacological therapy may yield some promise. It has also been deduced from these laboratory studies that hyperthermia is deleterious and rigorous measures to prevent hyperthermia should be taken to minimize the propagation of secondary neuronal damage after traumatic SCI.

Johnston, M. V. (2003). "Brain plasticity in paediatric neurology." Eur J Paediatr Neurol 7(3): 105-13.

            Plasticity includes the brain's capacity to be shaped or moulded by experience, the capacity to learn and remember, and the ability to reorganize and recover after injury. Mechanisms for plasticity include activity-dependent refinement of neuronal connections and synaptic plasticity as a substrate for learning and memory. The molecular mechanisms for these processes utilize signalling cascades that relay messages from synaptic receptors to the nucleus and the cytoskeleton to control the structure of axons and dendrites. Several paediatric neurological disorders such as neurofibromatosis-1, Fragile X syndrome, Rett syndrome, and other syndromic and non-specific forms of mental retardation involve lesions in these signalling pathways. Acquired disorders such as hypoxic-ischaemic encephalopathy, lead poisoning and epilepsy also involve signalling pathways including excitatory glutamate receptors. Information about these 'plasticity pathways' is useful for understanding their pathophysiology and potential therapy.

Kaushik, S., S. S. Pandav, et al. (2003). "Neuroprotection in glaucoma." J Postgrad Med 49(1): 90-5.

            Currently, glaucoma is recognised as an optic neuropathy. Selective death of retinal ganglion cells (RGC) is the hallmark of glaucoma, which is also associated with structural changes in the optic nerve head. The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage that is followed by a slower secondary degeneration related to noxious environment surrounding the degenerating cells. For example, retinal ishaemia may establish a cascade of changes that ultimately result in cell death: hypoxia leads to excitotoxic levels of glutamate, which cause a rise in intra-cellular calcium, which in turn, leads to neuronal death due to apoptosis or necrosis. Neuroprotection is a process that attempts to preserve the cells that were spared during the initial insult, but are still vulnerable to damage. Although not yet available, a neuroprotective agent would be of great use in arresting the progression of glaucoma. There is evidence that neuroprotection can be achieved both pharmacologically and immunologically. Pharmacological intervention aims at neutralising some of the effects of the nerve-derived toxic factors, thereby increasing the ability of the spared neurons to cope with stressful conditions. On the other hand, immunological interventions boost the body's own repair mechanisms for counteracting the toxic effects of various chemicals generated during the cascade. This review, based on a literature search using MEDLINE, focuses on diverse cellular events associated with glaucomatous neurodegeneration, and discusses some pharmacological agents believed to have a neuroprotective role in glaucoma.

Kim, K. S. (2003). "Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury." Nat Rev Neurosci 4(5): 376-85.

Kolb, B. (2003). "Overview of cortical plasticity and recovery from brain injury." Phys Med Rehabil Clin N Am 14(1 Suppl): S7-25, viii.

            The analysis of plastic changes in the nervous system is based on the assumption that the nervous system is not a static system but rather one that changes over time. Neural plasticity can be studied at many levels, beginning with behavior and then becoming progressively more microscopic by descending to the level of cerebral maps, synaptic organization, physiologic activities, molecular structure, and mitosis. This article considers each level in turn and then briefly describes how an understanding of the principles of plasticity can be used to initiate treatments for cerebral injury.

Kozorovitskiy, Y. and E. Gould (2003). "Adult neurogenesis: a mechanism for brain repair?" J Clin Exp Neuropsychol 25(5): 721-32.

            It is now generally accepted that new neurons are added to the adult mammalian brain. This raises the possibility that naturally occurring neurogenesis may be useful for repairing the damaged adult brain. Indeed, several studies have shown that damage to the adult brain can stimulate reparative neurogenesis. However, the production of new neurons is only one of several steps necessary to restore damaged neural circuits to their original state. Studies carried out on intact animals have identified several conditions that affect the production and survival of new neurons in adult brains. This review considers the evidence for compensatory neurogenesis in the adult mammalian brain with a view toward applying information from the undamaged brain to studies of regeneration.

Krishnan, R. V. (2003). "Spinal cord injury: inductive lability can enhance and hasten recovery." Int J Neurosci 113(6): 761-75.

            In spinal cord injury, recovery of function, if any, confirms the presence of survived neural tissue at the injury site. However, recovery several years after the injury remains unexplained. Body weight bearing locomotor exercises seem to bring these new outcomes. Developing locomotor system and computer simulation studies show that motor learning requires the presence of redundant sets of competing synapses within the spinal cord interneurons. The new exercise regimens have not addressed this essential prerequisite; this could perhaps explain the long delays in recovery. We recommend that inclusion of inductive lability procedure (Krishnan, 1983, 1991, 2003) will help hasten and enhance the recovery.

Kuroiwa, T. and R. Okeda (2003). "Checkpoints and pitfalls in the experimental neuropathology of circulatory disturbance." Neuropathology 23(1): 79-89.

            In neural tissue injury many pathological processes are common to different neurological disorders, including cerebral ischemia. Because ischemia has a fundamentally simple impact on neural tissue, good laboratory modeling can help improve the general understanding of the neuropathological processes involved. Summarized here are some basic principles that should be followed to ensure that cerebral ischemia studies are reproducible and informative: (i) selection of an appropriate model of cerebral ischemia in an appropriate species (although rodents are widely used for genomic studies, the use of larger animals, with brain structures macroscopically similar to those of humans, is appropriate for many studies, e.g. of white matter lesions or the pathophysiology of cerebral edema); (ii) correct maintenance of physiological parameters, including body temperature, systemic blood pressure, and blood gas tensions, under appropriate general anesthesia; (iii) selection of an appropriate method of cerebral blood flow (CBF) monitoring (decisions include whether or not the experiment requires real-time monitoring, in vivo measurement, and CBF mapping); (iv) appropriate timing of drug application in therapeutic studies (many drugs that are effective when given immediately after a short period of ischemia are ineffective in clinical trials, probably because of longer periods of ischemia and delayed drug delivery in clinical settings); and (v) multiparametric evaluation of therapeutic effect (with the recent increase in diagnosis of cases of mild stroke, measurement of mortality and infarct size have proven to be insufficient for the evaluation of therapeutic effect). Use of mild ischemia models and batteries of neurological tests for individual neurological functions, such as motor, somatosensory, and visual function, are becoming important in experimental ischemia research. In histological evaluation, assessment of the extent of both selective neuronal loss and the infarct will become mandatory. Regional analysis of each brain structure and coordination of the results with the apparent neurological dysfunction is a promising approach.

Lee, J. H. (2003). "Genetic evidence for cognitive reserve: variations in memory and related cognitive functions." J Clin Exp Neuropsychol 25(5): 594-613.

            Variations in cognitive functions across individuals are observed universally, and such observations serve as the basis of cognitive reserve (CR). Broadly, cognitive reserve refers to the inconsistency between neuropathology and clinical severity. The causes of such individual variations are likely to be multi-factorial. In this review, I present studies which suggest that genes are likely to be the contributing causes, and these genes interact with environmental factors to produce even greater variations in cognitive functions. A number of animal and human studies are beginning to reveal the role of genetic contributions to cognitive functions like memory, memory decline, general intelligence, and language. Twin studies suggest that there is a substantial heritable component for memory and related cognitive functions, such as general intelligence and language, but not for others. Thus, heritability estimates vary by cognitive domain. Animal studies and some human studies have identified genes or candidate loci that contribute to memory as well as other related cognitive phenotypes. Yet, our current understanding is limited. It will require interdisciplinary efforts from a number of different fields to better define the neuropsychological phenotype. At the same time, it is necessary to take into account both genetic and environmental factors to understand the complex network underlying CR.

Levin, H. S. (2003). "Neuroplasticity following non-penetrating traumatic brain injury." Brain Inj 17(8): 665-74.

            The primary objective of this review is to examine the methodology and evidence for neuroplasticity operating in recovery from traumatic brain injury (TBI), as compared with previous findings in patients sustaining perinatal and infantile focal vascular lesions. The evidence to date indicates that the traditional view of enhanced reorganization of function after early focal brain lesions might apply to early focal brain lesions, but does not conform with studies of early severe diffuse brain injury. In contrast to early focal vascular lesions, young age confers no advantage in the outcome of severe diffuse brain injury. Disruption of myelination could potentially alter connectivity, a suggestion which could be confirmed through diffusion tensor imaging (DTI). Initial reports of DTI in TBI patients support the possibility that this technique can demonstrate alterations in white matter connections which are not seen on conventional magnetic resonance imaging (MRI) and might change over time or with interventions. Preliminary functional MRI studies of TBI patients indicate alterations in the pattern of brain activation, suggesting recruitment of more extensive cortical regions to perform tasks which stress computational resources. Functional MRI, coupled with DTI and possibly other imaging modalities holds the promise of elucidating mechanisms of neuroplasticity and repair following TBI.

Li, Y. and C. Owyang (2003). "Musings on the wanderer: what's new in our understanding of vago-vagal reflexes? V. Remodeling of vagus and enteric neural circuitry after vagal injury." Am J Physiol Gastrointest Liver Physiol 285(3): G461-9.

            The vago-vagal reflexes mediate a wide range of digestive functions such as motility, secretion, and feeding behavior. Previous articles in this series have discussed the organization and functions of this important neural pathway. The focus of this review will be on some of the events responsible for the adaptive changes of the vagus and the enteric neutral circuitry that occur after vagal injury. The extraordinary plasticity of the neural systems to regain functions when challenged with neural injury will be discussed. In general, neuropeptides and transmitter-related enzymes in the vagal sensory neurons are downregulated after vagal injury to protect against further injury. Conversely, molecules previously absent or present at low levels begin to appear or are upregulated and are available to participate in the survival-regeneration process. Neurotrophins and other related proteins made at the site of the lesion and then retrogradely transported to the soma may play an important role in the regulation of neuropeptide phenotype expression and axonal growth. Vagal injury also triggers adaptive changes within the enteric nervous system to minimize the loss of gastrointestinal functions resulting from the interruption of the vago-vagal pathways. These may include rearrangement of the enteric neural circuitry, changes in the electrophysiological properties of sensory receptors in the intramural neural networks, an increase in receptor numbers, and changes in the affinity states of receptors on enteric neurons.

Liu, B., H. M. Gao, et al. (2003). "Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation." Environ Health Perspect 111(8): 1065-73.

            Idiopathic Parkinson's disease (PD) is a devastating movement disorder characterized by selective degeneration of the nigrostriatal dopaminergic pathway. Neurodegeneration usually starts in the fifth decade of life and progresses over 5-10 years before reaching the fully symptomatic disease state. Despite decades of intense research, the etiology of sporadic PD and the mechanism underlying the selective neuronal loss remain unknown. However, the late onset and slow-progressing nature of the disease has prompted the consideration of environmental exposure to agrochemicals, including pesticides, as a risk factor. Moreover, increasing evidence suggests that early-life occurrence of inflammation in the brain, as a consequence of either brain injury or exposure to infectious agents, may play a role in the pathogenesis of PD. Most important, there may be a self-propelling cycle of inflammatory process involving brain immune cells (microglia and astrocytes) that drives the slow yet progressive neurodegenerative process. Deciphering the molecular and cellular mechanisms governing those intricate interactions would significantly advance our understanding of the etiology and pathogenesis of PD and aid the development of therapeutic strategies for the treatment of the disease.

Lythgoe, M. F., N. R. Sibson, et al. (2003). "Neuroimaging of animal models of brain disease." Br Med Bull 65: 235-57.

            The main aim of this review is to describe some of the many animal models that have proved to be valuable from a neuroimaging perspective. This paper complements other articles in this volume, with a focus on animal models of the pathology of human brain disorders for investigations with modern non-invasive neuroimaging techniques. The use of animal model systems forms a fundamental part of neuroscience research efforts to improve the prevention, diagnosis, understanding and treatment of neurological conditions. Without such models it would be impossible to investigate such topics as the underlying mechanisms of neuronal cell damage and death, or to screen compounds for possible anticonvulsant properties. The adequacy of any one particular model depends on the suitability of information gained during experimental conditions. It is important, therefore, to understand the various types of animal model available and choose an appropriate model for the research question.

Maiese, K. and Z. Z. Chong (2003). "Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain." Trends Pharmacol Sci 24(5): 228-32.

            Although usually identified as an essential cellular nutrient for cellular growth and maintenance, nicotinamide is under development as a novel cytoprotectant for acute and chronic neurodegenerative disorders. Here, we outline support for the premise that nicotinamide both prevents and reverses neuronal and vascular cell injury. Nicotinamide fosters DNA integrity and maintains phosphatidylserine membrane asymmetry to prevent cellular inflammation, cellular phagocytosis and vascular thrombosis. The downstream cellular and molecular cascades are considered vital for the cytoprotection offered by nicotinamide. These pathways encompass the modulation of Akt, the forkhead transcription factor FKHRL1, mitochondrial membrane potential, caspase activities and cellular energy metabolism, but remain independent of intracellular pH and mitogen-activated protein kinases. As both a therapeutic agent and an investigational tool, nicotinamide offers new therapeutic strategies for degenerative disorders of the CNS.

Marcus, A. J., M. J. Broekman, et al. (2003). "Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases." J Pharmacol Exp Ther 305(1): 9-16.

            Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion (thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39-an ecto-ADPase-reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP (thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. "Reconstitution" of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses.

Mattson, M. P., W. Duan, et al. (2003). "Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms." J Neurochem 84(3): 417-31.

            Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.

McGee, A. W. and S. M. Strittmatter (2003). "The Nogo-66 receptor: focusing myelin inhibition of axon regeneration." Trends Neurosci 26(4): 193-8.

            CNS myelin inhibits axonal outgrowth in vitro and is one of several obstacles to functional recovery following spinal cord injury. Central to our current understanding of myelin-mediated inhibition are the membrane protein Nogo and the Nogo-66 receptor (NgR). New findings implicate NgR as a point of convergence in signal transduction for several myelin-associated inhibitors. Additional studies have identified a potential coreceptor for NgR as p75(NTR), and a second-messenger pathway involving RhoA that inhibits neurite elongation. Although these findings expand our understanding of the molecular determinants of adult CNS axonal regrowth, the physiological roles of myelin-associated inhibitors in the intact adult CNS remain ill-defined.

Meiners, S. and M. L. Mercado (2003). "Functional peptide sequences derived from extracellular matrix glycoproteins and their receptors: strategies to improve neuronal regeneration." Mol Neurobiol 27(2): 177-96.

            Peptides derived from extracellular matrix proteins have the potential to function as potent therapeutic reagents to increase neuronal regeneration following central nervous system (CNS) injury, yet their efficacy as pharmaceutical reagents is dependent upon the expression of cognate receptors in the target tissue. This type of codependency is clearly observed in successful models of axonal regeneration in the peripheral nervous system, but not in the normally nonregenerating adult CNS. Successful regeneration is most closely correlated with the induction of integrins on the surface of peripheral neurons. This suggests that in order to achieve optimal neurite regrowth in the injured adult CNS, therapeutic strategies must include approaches that increase the number of integrins and other key receptors in damaged central neurons, as well as provide the appropriate growth-promoting peptides in a "regeneration cocktail." In this review, we describe the ability of peptides derived from tenascin- C, fibronectin, and laminin-1 to influence neuronal growth. In addition, we also discuss the implications of peptide/receptor interactions for strategies to improve neuronal regeneration.

Mitchell, G. S. and S. M. Johnson (2003). "Neuroplasticity in respiratory motor control." J Appl Physiol 94(1): 358-74.

            Although recent evidence demonstrates considerable neuroplasticity in the respiratory control system, a comprehensive conceptual framework is lacking. Our goals in this review are to define plasticity (and related neural properties) as it pertains to respiratory control and to discuss potential sites, mechanisms, and known categories of respiratory plasticity. Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. Respiratory neuroplasticity is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, the balance between opposing modulatory systems, age, gender, and genetics. Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury, stress, and pharmacological interventions or conditioning and occurs during development as well as in adults. Developmental plasticity is induced by experiences (e.g., altered respiratory gases) during sensitive developmental periods, thereby altering mature respiratory control. The same experience later in life has little or no effect. In adults, neuromodulation plays a prominent role in several forms of respiratory plasticity. For example, serotonergic modulation is thought to initiate and/or maintain respiratory plasticity following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory denervation, spinal cord injury, and at least some conditioned reflexes. Considerable work is necessary before we fully appreciate the biological significance of respiratory plasticity, its underlying cellular/molecular and network mechanisms, and the potential to harness respiratory plasticity as a therapeutic tool.

Moris, G. and J. A. Vega (2003). "[Neurotrophic factors: basis for their clinical application]." Neurologia 18(1): 18-28.

            Neurotrophic factors are molecules that regulate neuronal survival, nervous system plasticity and many other physiological functions of neuronal and glial cells, as well as some non-neuronal tissues. They have been involved in the etiopathogenesis of some neurodegenerative disorders, and some of them have been proposed as potential treatments for these diseases on the basis of in vitro experiments and animal models. The main neurotrophic factor families with potential therapeutic applications include the family of neurotrophins (NGF, BDNF or NT-3), GDNF and related neurotrophic factor, CNTF and the members of the IGF family. Some of these molecules have already been tested in clinical trials with contradictory results. One of the major challenges to their clinical use is the difficulty to deliver them into the central nervous system. Nevertheless, solid rational exists for the possible use of neurotrophic factors in the treatment of Alzheimer's and Parkinson's diseases, peripheral neuropathies or amyotrophic lateral sclerosis. This review compiles the essential aspects of neurotrophic factors and the current studies of their clinical relevance and therapeutic potentialities. Future directions for further research are also discussed.

Morris, K. F., D. M. Baekey, et al. (2003). "Invited review: Neural network plasticity in respiratory control." J Appl Physiol 94(3): 1242-52.

            Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.

Morrison, R. S., Y. Kinoshita, et al. (2003). "p53-dependent cell death signaling in neurons." Neurochem Res 28(1): 15-27.

            The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to multiple forms of cellular stress. p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from animal models and patients with chronic neurodegenerative diseases. p53 deficiency or p53 inhibition protects neurons from a wide variety of acute toxic insults. Signal transduction pathways associated with p53-induced neuronal cell death are being characterized, suggesting that intervention may prove effective in maintaining neuronal viability and restoring function following neural injury and disease.

Nudo, R. J., D. Larson, et al. (2003). "A squirrel monkey model of poststroke motor recovery." Ilar J 44(2): 161-74.

            Nonhuman primate models of poststroke recovery have become increasingly rare primarily due to high purchase and maintenance costs and limited availability of nonhuman primate species. Despite this obstacle, nonhuman primate models may offer important advantages over rodent models for understanding many of the brain's mechanisms for self-repair due to greater similarity in cortical organization to humans. Since the mid-1990s, surgical, neurophysiological, and neuroanatomical methods have been developed to understand structural and functional remodeling of the cerebral cortex after an ischemic event, such as occurs in stroke. These methods require long surgical procedures and entail constant physiological monitoring. With careful attention to intraoperative and postsurgical monitoring, these procedures can be repeated multiple times in individual monkeys without untoward events. This model provides a statistically powerful approach for tracking brain plasticity in the ensuing weeks and months after a stroke-like injury, reducing the number of animals required for individual experiments. This methodology is described in detail, and many of the resulting findings that are relevant for understanding stroke recovery and the effects of rehabilitative and pharmacotherapeutic interventions are summarized.

Nudo, R. J. (2003). "Functional and structural plasticity in motor cortex: implications for stroke recovery." Phys Med Rehabil Clin N Am 14(1 Suppl): S57-76.

            Several studies have now demonstrated that the motor cortical representations are dynamically maintained in both normal and brain-injured animals. Functional plasticity in the motor cortex of normal animals is accompanied by changes in synaptic morphology; these changes are skill-dependent rather than simply use-dependent. Finally, motor cortical areas undergo substantial functional alterations after focal ischemic infarcts; motor experience is a potent and adaptive modulator of injury-related plasticity. These recent neuroscientific advances set the stage for the development of new, more effective interventions in chronic stroke populations that are based on the basic mechanisms underlying neuroplasticity.

Patel, H. C., H. Boutin, et al. (2003). "Interleukin-1 in the brain: mechanisms of action in acute neurodegeneration." Ann N Y Acad Sci 992: 39-47.

            Interleukin-1 (IL-1) exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. Much of this is based on studies using the IL-1 receptor antagonist, which inhibits cell death caused by ischemia, brain injury, or excitotoxins. Our aim is to determine how and where in the brain IL-1 acts to produce these effects. Most of the neurodegenerative effects of IL-1 are thought to be through IL-1 beta. However, we have data implicating IL-1 alpha in excitotoxic cell death. Furthermore mice lacking both IL-1 alpha and IL-1 beta show dramatically reduced ischemic cell death, whereas deletion of IL-1 alpha or IL-1 beta alone fails to modify damage. It has also been demonstrated that IL-1 exacerbates ischemic injury in mice in the absence of the type I IL-1 receptor, suggesting the existence of novel IL-1 receptors in the brain. IL-1 also dramatically exacerbates neuronal loss in response to intrastriatal administration of the excitotoxin AMPA in the rat brain, an effect accompanied by marked increases in cytokine expression in the frontoparietal cortex, which precedes subsequent cell death in this region. Intrastriatal AMPA also results in limbic seizures that are exacerbated by IL-1, and we hypothesize, therefore, that IL-1 exacerbates cell death through increased seizure activity. Therefore, IL-1 appears to induce acute neurodegeneration through a number of mechanisms.

Payne, J. A., C. Rivera, et al. (2003). "Cation-chloride co-transporters in neuronal communication, development and trauma." Trends Neurosci 26(4): 199-206.

            Electrical signaling in neurons is based on the operation of plasmalemmal ion pumps and carriers that establish transmembrane ion gradients, and on the operation of ion channels that generate current and voltage responses by dissipating these gradients. Although both voltage- and ligand-gated channels are being extensively studied, the central role of ion pumps and carriers is largely ignored in current neuroscience. Such an information gap is particularly evident with regard to neuronal Cl- regulation, despite its immense importance in the generation of inhibitory synaptic responses by GABA- and glycine-gated anion channels. The cation-chloride co-transporters (CCCs) have been identified as important regulators of neuronal Cl- concentration, and recent work indicates that CCCs play a key role in shaping GABA- and glycine-mediated signaling, influencing not only fast cell-to-cell communication but also various aspects of neuronal development, plasticity and trauma.

Pellegrini-Giampietro, D. E. (2003). "The distinct role of mGlu1 receptors in post-ischemic neuronal death." Trends Pharmacol Sci 24(9): 461-70.

            Metabotropic glutamate receptors of the mGlu(1) and mGlu(5) subtypes exhibit a high degree of sequence homology and are both coupled to phospholipase C and intracellular Ca(2+) mobilization. However, functional differences have been detected for these receptor subtypes when they are coexpressed in the same neuronal populations. Experimental evidence indicates that mGlu(1) and mGlu(5) receptors play a differential role in models of cerebral ischemia and that only mGlu(1) receptors are implicated in the pathways leading to post-ischemic neuronal injury. The localization of mGlu(1) receptors in GABA-containing interneurons rather than in hippocampal CA1 pyramidal cells that are vulnerable to ischemia has prompted studies that have provided a new viewpoint on the neuroprotective mechanism of mGlu(1) receptor antagonists. The hypothesis predicts that these pharmacological agents attenuate post-ischemic injury by enhancing GABA-mediated neurotransmission.

Perez Velazquez, J. L., M. V. Frantseva, et al. (2003). "Gap junctions and neuronal injury: protectants or executioners?" Neuroscientist 9(1): 5-9.

            The authors review concepts and recent experimental observations that relate gap junctional communication to the pathophysiology of neuronal injury, specifically ischemic or traumatic damage. The role played by this type of direct intercellular communication during the progression of the injuries can be conceived to be either detrimental or beneficial, depending on the arguments employed. The data indicate that, far from being a simple matter of judgment, the contribution of gap junctions to cell injury is a complicated phenomenon that depends on the specific insult and network in which it operates.

Phillis, J. W. and M. H. O'Regan (2003). "The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries." Crit Rev Neurobiol 15(1): 61-90.

            Free fatty acids (FFAs) are elevated in the brain following both ischemic and traumatic injury. Phospholipase activation, with the subsequent release of FFAs from membrane phospholipids, is the likely mechanism. In addition to phospholipases A1, B, C, and D, there are at least 19 groups of PLA2, including multiple cytosolic, calcium independent, and secretory isoforms. Phospholipase activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. These enzymes normally function in the physiological remodeling of cellular membranes, whereby FFAs are removed by phospholipase activity and then reacylated with a different FFA. However, reductions in the cell's ability to maintain normal metabolic function and the resultant fall in ATP levels can cause the failure of reacylation of membrane phospholipids. Alterations to membrane phospholipids would be expected to compromise many cellular functions, including the ability to accumulate excitotoxic amino acids. This review presents evidence for a central role of phospholipases and their products in the etiology of damage following injury to the brain. Phospholipase expression and activity is increased in animal models of cerebral ischemia and trauma. FFA release from the in vivo rat brain is reduced following the application of selective phospholipase inhibitors, and this inhibition also decreases the severity of cortical damage following forebrain ischemia, focal (middle cerebral artery occlusion) ischemia, and cerebral trauma. Mice with knockouts of PLA2 have decreased infarct volumes. Human data demonstrate a correlation between the elevation of CSF FFAs and worsened outcome following stroke, traumatic brain injury, and subarachnoid hemorrhage. The released FFAs, especially arachidonic and docosahexaenoic acids, together with the production of lysophospholipids, can initiate a chain of events which may be responsible for the development of neuronal damage. Inhibitors of both cyclooxygenase and lipoxygenase pathways have been shown to reduce cerebral deficits following ischemia and trauma. These results suggest therapeutic strategies to reduce morbidity following cerebral injury using selective inhibitors of phospholipases, cyclooxygenases, and lipoxygenases, underlining the need for further investigation of their role in the development of cerebral damage.

Phillis, J. W. and M. H. O'Regan (2003). "Characterization of modes of release of amino acids in the ischemic/reperfused rat cerebral cortex." Neurochem Int 43(4-5): 461-7.

            Brain extracellular levels of glutamate, aspartate, GABA and glycine increase rapidly following the onset of ischemia, remain at an elevated level during the ischemia, and then decline over 20-30 min following reperfusion. The elevated levels of the excitotoxic amino acids, glutamate and aspartate, are thought to contribute to ischemia-evoked neuronal injury and death. Calcium-evoked exocytotic release appears to account for the initial (1-2 min) efflux of neurotransmitter-type amino acids following the onset of ischemia, with non-vesicular release responsible for much of the subsequent efflux of these and other amino acids, including taurine and phosphoethanolamine. Extracellular Ca(2+)-independent release is mediated, in part by Na(+)-dependent amino acid transporters in the plasma membrane operating in a reversed mode, and by the opening of swelling-induced chloride channels, which allow the passage of amino acids down their concentration gradients. Experiments on cultured neurons and astrocytes have suggested that it is the astrocytes which make the primary contribution to this amino acid efflux. Inhibition of phospholipase A(2) attenuates ischemia-evoked release of both amino and free fatty acids from the rat cerebral cortex indicating that this group of enzymes is involved in amino acid efflux, and also accounting for the consistent ischemia-evoked release of phosphoethanolamine. It is, therefore, possible that disruption of membrane integrity by phospholipases plays a role in amino acid release. Recovery of amino acid levels to preischemic levels requires their uptake by high affinity Na(+)-dependent transporters, operating in their normal mode, following restoration of energy metabolism, cell resting potentials and ionic gradients.

Powner, D. J. (2003). "Effects of gene induction and cytokine production in donor care." Prog Transplant 13(1): 9-14; quiz 15-6.

            Gene induction, cytokine production, and programmed neuronal and myocardial cell death are concerns that have entered the areas of donor evaluation and care over the past several years. Following ischemic or traumatic brain injury and the evolution of brain death, a large number of proteins (cytokines) are produced as part of a regional inflammatory response. These cytokines and related compounds appear to contribute to programmed death (apoptosis) of individual cells and the severe cardiac and hemodynamic changes often encountered during donor care. In addition, these cytokines and related compounds may sensitize donor organs so that a faster and more severe form of rejection occurs in the recipient. Although no directed therapy for these cytokine effects is presently available, the organ procurement coordinator should be aware of these issues and concerns as new treatment options evolve in the near future.

Prins, M. L. and D. A. Hovda (2003). "Developing experimental models to address traumatic brain injury in children." J Neurotrauma 20(2): 123-37.

            Traumatic brain injury (TBI) is the leading cause of injury-related death and disability among children under the age of 15 years in the United States. Epidemiological studies have revealed that even within the pediatric population there are differences in incidence, gender differences, causes, types of injuries sustained, and mortality within age subdivisions. This heterogeneity must be taken into account when developing appropriate models to address TBI in children. This review explores the current developmental TBI models, including fluid percussion, weight drop, and controlled cortical impact. It also addresses unique considerations to modeling pediatric brain injury that require special attention when modeling and designing studies: age appropriateness, injury severity, evaluation of recovery, plasticity, and anesthesia.

Ray, S. K., E. L. Hogan, et al. (2003). "Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors." Brain Res Brain Res Rev 42(2): 169-85.

            Spinal cord injury (SCI) evokes an increase in intracellular free Ca(2+) level resulting in activation of calpain, a Ca(2+)-dependent cysteine protease, which cleaves many cytoskeletal and myelin proteins. Calpain is widely expressed in the central nervous system (CNS) and regulated by calpastatin, an endogenous calpain-specific inhibitor. Calpastatin degraded by overactivation of calpain after SCI may lose its regulatory efficiency. Evidence accumulated over the years indicates that uncontrolled calpain activity mediates the degradation of many cytoskeletal and membrane proteins in the course of neuronal death and contributes to the pathophysiology of SCI. Cleavage of the key cytoskeletal and membrane proteins by calpain is an irreversible process that perturbs the integrity and stability of CNS cells leading to cell death. Calpain in conjunction with caspases, most notably caspase-3, can cause apoptosis of the CNS cells following trauma. Aberrant Ca(2+) homeostasis following SCI inevitably activates calpain, which has been shown to play a crucial role in the pathophysiology of SCI. Therefore, calpain appears to be a potential therapeutic target in SCI. Substantial research effort has been focused upon the development of highly specific inhibitors of calpain and caspase-3 for therapeutic applications. Administration of cell permeable and specific inhibitors of calpain and caspase-3 in experimental animal models of SCI has provided significant neuroprotection, raising the hope that humans suffering from SCI may be treated with these inhibitors in the near future.

Reynolds, L. P. and G. V. Allen (2003). "A review of heat shock protein induction following cerebellar injury." Cerebellum 2(3): 171-7.

            Exposure of cells to stressful environments such as heat shock, ischemia, trauma and disease, induces the cellular expression of heat shock proteins (Hsps). Since the discovery of heat shock proteins in the early 1960s, efforts to understand their function in both stressed and non-stressed cells have remained the focus of a vast collection of researchers. Post-injury heat shock protein induction is believed to identify regions of reversible cell injury as well as contribute to repair and protective mechanisms following stress. With the role of cerebellum expanding to include a number of cognitive processes in addition to contributing to motor coordination, research contributions that further our understanding of cerebellar repair strategies following injury are significant. Following cellular stress, heat shock protein expression was observed in both neuronal and glial cell populations in the injured cerebellum. Specifically, Hsp27 expression was localized primarily in Purkinje cells and glial cells within the injured cerebellum, whereas Hsp72 induction was more prominent in the granule cell layer of the cerebellum. Thus, there appears to be a preferential expression of different families of heat shock proteins in different cell populations in the injured cerebellum. There are also distinct post-injury time frames of induction for each family of heat shock protein, emphasizing differences in cellular functional requirements for each family of heat shock protein. Hsp27 was expressed immediately following injury and continued up to 20 days post-injury whereas Hsp72 was expressed immediately following injury and disappeared by 4 days post-injury, suggesting the latter contributes to processes involved in the initial repair of injured cells. This review discusses heat shock protein induction patterns in both in vivo and in vitro cerebellar injury models and provides suggestions as to the functional role of heat shock proteins in the injured cerebellum.

Rhodes, J. K. (2003). "Actions of glucocorticoids and related molecules after traumatic brain injury." Curr Opin Crit Care 9(2): 86-91.

            PURPOSE OF REVIEW: Despite 25 years of randomized, controlled trials, the benefit of steroid administration to patients with traumatic brain injury is unproved. Traditionally, glucocorticoids have been used empirically to reduce inflammation and edema. However, it is becoming apparent that the mechanisms by which steroid molecules might act to improve recovery after traumatic brain injury are numerous. RECENT FINDINGS: The effects of steroid administration on the central nervous system are not uniform but depend on the population of neurons studied. Definite deleterious effects of steroid administration on neuronal survival have been described. SUMMARY: This review discusses why glucocorticoids might be effective, the considerable laboratory evidence supporting the use of 21-aminosteroids, and the potentially harmful effects of steroid molecules on the brain.

Rivest, S. (2003). "Molecular insights on the cerebral innate immune system." Brain Behav Immun 17(1): 13-9.

            All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction